Z-alkyl-j-amino-s-pykazolones



Patented Oct. 24, 1944 2-ALKYL3 -AMINO --PYRAZOLON ES Hans Stenzl and Alfred Staub, Basel, Switzerland,

assignors to J. R. Geigy A. G., Basel, Switzerland No Drawing. Application January 13, 1942, Se-

rial No. 426,638. In Switzerland July 31, 1941 g 5 Claims. (01. 2641-310) It has been found that, according to the usual processes of decomposition for the transformation of the carboxyl c group into the amino group, there can be produced new valuable 3-aminopyrazolones as well as their carbalkoxy' or carbamide derivatives from 2-alkyl-5-pyrazolone-3- carboxylic acids of the formula oo-'-o-R3 R1N1/ 5 4 2 3 N--COOOH 1 12 wherein R1 means an aliphatic, araliphatic, hydroaromatic or aromatic radical, R2 means an aliphatic radical and R3 means hydrogen, halogen, an aliphatic, a saturated or unsaturated cycloaliphatic, an aromatic or an araliphatic radical, or from their suitable functional derivatives. The said compounds show distinctly antipyretical eiTects and, in contradistinction .to the other pyrazolones used for therapeutic purposes, are substantially tasteless. The urethanes resulting as intermediate products in this manufacture in the presence of alcohols are especially efficacious,

but on the other hand the corresponding-urea derivatives may also be mentioned.

For the replacement of the carboxyl group by the amino group or substituted amino group the processes according to Hofmann .and Curtius:

acids of the type:

the hydrazides are advantageously obtained in the usual manner by the reaction of hydrazine. They are colorless, high-melting compounds which, for the most part, are difficultly soluble in Water. Only in those cases where, in the positions l or 3, there stands a methyl group, the corresponding hydrazide is very easily soluble in water, but very diificultly soluble in absolute alcohol. By means of nitrite the hydrazides are converted in acid solution into the azides, which immediately precipitate out from the aqueous solution in form of a yellow crystalline powder which is somewhat sensitive to light. Only if in 4-position there is a methyl group, the azide is easily soluble in water and must then be shaken out with an organic solvent such as for example chloroform. At about C. the azides are stormily decomposed-while in solution the same are decomposed already at a, substantially lower temperature.

The azides can also be prepared directly from the halides of the corresponding acids by interaction with sodium azide. It is not necessary to isolate them in substance; instead thereof one can immediately dissolve them in a suitable solvent. for instance chloroform, dry the solution and boil it, after addition of an alcohol, until the azide is completely converted. The hydrazides can also be dissolved in alcoholic hydrochloric acid and, after introduction of ethyl nitrite and some standing, the formed azide can be converted by boiling intothe urethane. The so-called shortened Curt us process (see Braun, Ber. 64 (1931) 2866 and British Patent 307,798) may also be used, but, in general, the method of isolation of the azide is preferable.

With respect to Hofmanns decomposing process there is to be mentioned that the same is facilitated in that the intermediarily formed halogen amides can, if desired, easily be isolated;

they are strong acids with good crystallising properties.

The products of both the decomposition processes are colorless, well crystallised compounds. The urethanes are weak acids which readily dissolve in d lute caustic lye, but difficultly in ether. The 3-aminopyrazolones may be obtained therefrom by acid as well as by alkaline saponification. vIn Hofmanns decomposition process the said compounds can be obtained directly without isolation of the intermediate products.

The 3-aminopyrazolones are weak bases which, in contradistinction to the l-aminoantipyrine, are rather difiicultly soluble in water and absolutely stable to air. They mostly melt at about 200 C. and more. With ferric chloride they yield in alcoholic solution a red-brown coloration.

It is true that other processes of decomposition which have become known, e. g. over the corresponding hydroxamic acids lead also to these products; but they may notcome into consideration for a technical preparation thereof.

The starting materials, the 2-alkyl-5-pyrazolone-3-carboxylicv acids or their esters, amides or hydrazides, as far as they are now known, can be prepared according to usual processes, but preferably by means of alkylation of the 5-pyrazunsubstituted in the 2-position. The esters may easily be obtained as well crystallized, weak bases,

their melting points are between 70 C. and 110 C., if in the 1-position there stands a radical of the benzene series.

The -pyrazolone-3-carboxylic acid compounds coming into consideration for the preparation of the 2-alkyl-5-pyrazoline3carboxylic acid compounds are easily accessible from the corresponding oxalacetic" acid esters. .However, the 1-phenylA-hydroxypropyl-5-pyrazolone -3- carboxylic acid ester can also, readily be obtained from 1-phenyl-5-pyrazolone-3-carboxylic acid ester by hydrogenation in the presence-of acetone, analogously the corresponding 4-sec. butyl derivative can be obtained. The 1-'phenyl-2-methyl- 4-bromo-5 pyrazolone-B-carboxylic acid ester can, analogously to the 4-bromo-antipyrine, be directly obtained from the bromine-free ester. Also the 1-phenyl-4-allyl-5epyrazolone-Zi-carboxylic acid este is obtainable by direct allylation of the 1--phenyl-5-pyrazolone-3-carboxylic acid ester, but 'in this case the synthesis .from allylacetic acid e'sterthrough-the oxalallyl-acetic acid esteris'tmbe preferred. 7

Hydrazides of pyrazolone compounds,.however, are already known, but their transformation .to the corresponding amines has .hitherto not yet .beencarriedsout. .AccordingtoKufferath (J. pr. Ch. 64, 337 the transformation of the pyrazolone- 3-acetic acid hydrazide .gives vnoresult. From the fact that, on theother hand, themethod of transformation 10f Curtiusis usable ior the pylowing examples, the parts .being by weight. where nothing other .is said.

Example "1 1.00 parts of "1 phenyl- 2-methyl-5-pyrazolonej3-carboxylio acid hydrazide (M. P. 233 C.), ob-

tained by digesting the ethyl ester with hydrazine hydrate, are dissolvedin .600 parts of 2n-hydrochloric acid, whereupon .a solution of 60 parts of sodium nitrite in .30'0parts of water is slowly added thereto. at .5 .C.; the azide of the 1 ,phenyl-2-methyl 5 pyrazolone-3-carboxylic acid immediately precipitates out in form of a yellow crystal sand. 'It is filtered, carefully washed out with water and dried :at a slow temperature (M. P. .95 0., decomposition). The azide thus obtainedis dissolved in 10parts of absolutealcohol and slowly warmed. At about "60 C. the nitrogen development'beginsto take place; as soon as this development diminishes, the whole is heated .to boiling, whereby l-phenyl- 2-methyl 3 carbethoxy-amino 5 pyrazolone l vIf, in Exam le 1, the absolute alcohol is replaced'by n-butyl alcohol, one obtains 1-phenylwhich is difficultly soluble in water.

2 methyl-3-carbo n-butoxyamino-5-pyrazolone in form of a crystal powder which can be recrystallised from dilute acetic acid or butyl alcohol (M. P. 194 0.).

Example 3 If, in Example 1, the ethyl alcohol is replaced by anhydrous glycol and if, after completion of the nitrogendevelopment, the whole is diluted with water, 1-phenyl-2-methyl-3-carbo-hydroxyethoxy-amino-5-pyrazolone precipitates out; when crystallised from dilute alcohol, it is obtained in form of colorless little leaves of melting point 212 C.

Example 4 by meansof absolute alcohol and the l-phenyl- .2-.ethyl 3-carbo-isopropyloxy-amino 5 pyrazolone ..(M.1,P. 211 C.) by means of isopropyl a1- -cohol.

From both esters there is readily produced by boiling with 2n-caustic soda lye 1-phenyl-2-ethyl- 3-amino-5-pyrazolone of melting point 226 C., which is difiicultly soluble in water, but easily soluble in alcohol.

Example 5 1 part of 1-phenyl-2-methyl-4-bromo-5-pyrazolone-3-carboxylic acid hydrazide (M. P. 183 C.) is dissolved in 6 parts of 2n-hydrochloric acid and then /3 part of sodium nitrite, dissolved in 2 parts of water, is mixed therewith at -.5 C. The azide precipitates out inform of a yellow sand which detonates at 104 C. By boiling the azide with 10 parts of methyl alcohol,

evaporating the methyl alcohol and then adding water thereto one obtains the l-phenyl-z-methyl- .3 -.carbomethoxy -.amino 4 bromopyrazolone which is easily soluble in methanol and melts at 104 C.

Example .6

From 1 phenyl 2:4 dimethyl 5 pyrazolone-3-carbcxylic acid ethyl ester (M. P. 96 C.) there is obtained, by interaction with hydrazine hydrate (for 6 hours at 100 C.), the l-phenyl- 2 :4-dimethyl-5-pyrazolone-3-carboxylic acid hydrazide (M. P. 158159 C.), which is easily soluble in water and difficultly soluble in absolute alcohol. Analogously to Example 1, there can be produced therefrom: 1-phenyl-2 4-dimethyl- 3- carbomethoxy-amino-S-pyrazolone (M. P. 188 189 C.), which is difficultly soluble in methanol, and 1 phenyl 2 4 dimethyl Z-carbo-isopropyloxy amino 5 pyrazolone (M. P. =15? C.)

From both urethanes there results the l-phenyl- 2:4-dimethyl-3-amino-5-pyrazolone (M. P. 196 C.) by the action of boiling dilute caustic soda lye.

Example 7 1- phenyl 2 methyl 4 ethyl 5 pyrazo 'lone 3-carboxylic acid ethyl ester (M; P. 72 C.)

is converted into the hydrazide (M. P. C.)

This compound is transformed,.as indicated in Example 1,

.into the azide and then by heating with methanol into the 1-pheny1-2-methy1-3 carbomethoxyamino-4-ethyl-5-pyrazolone of melting point 144 C. This urethane is easily .soluble in alcohol.

I By boiling the said urethane with caustic soda lye there is obtained the 1-phenyl-2-methyl-3- -amino-4-ethyl-5-pyrazolone of melting point Example 8 1 phenyl 2 methyl 4 isopropyl pyrazolone-B-carboxylic acid ethyl ester.(M. P. 73 C., made from l-phenyl-5-pyrazolone-3-carboxylicacid ethyl ester by hydrogenation in acetone tinder a pressure of 50 atm. at 110 C. and subsequent methylation) is converted by heating with hydrazine,-into the hydrazide (M. P. 113115 C.

when crystallised from water) and the same, as

described in Example 1, transformed into the azide (M. Rev-90? 0.). By heating with the corresponding alcohols one obtains:

1 phenyl -'2 methyl 3 carbomethoxy amino-4-isopropyl-5-pyraz0lone, -M. P. 126 C., when crystallised from an alcohol-ether mixture;

1 phenyl 2 methyl 3 carbethoxy amino- 4-isopropyl-5-pyrazolone, M. P. 141-142 C.;

1 phenyl 2 methyl 3 carbo allyloxy-ami no-4-isopropyl-5-pyrazolone, M. P. 102 C.;

l phenyl 2 methyl 3 carbo isopropyloxyamino-3-isopropyl-5-pyrazolone, M. P. 139/ 140 C.;

1-phenyl-2-methyl-S-carbo-chloroethoxy amino-4-isopropy1-5-pyrazolone, M. P. 135 0.;

1 phenyl 2 methyl 3 carbo hydroxyethoxy amino-4-isopropyl-5-pyrazolone, M. P. 136 C.

From all the aforesaid urethanes there result, by means of boiling dilute caustic soda lye, the 1- phenyl 2 methyl 3 amino 4 isopropyl 5-pyrazolone which, when crystallised from dilute alcohol, shows a melting point of 204 C.

Example 9 56 parts of 1phenyl-2-methyl-4-isopropyl-5- pyrazolone-3-carboxylic acid hydra-zide are dissolved in 400 parts of methyl alcoholic hydro chloric acid of 13 per cent strength and 20 parts of methyl nitrite dissolved in 200 parts of metha- 1101 are dropped thereto at 0C. After a standing for 12 hours at room temperature the methyl alcohol is slowly distilled off, the residue solidifies onadding water thereto to a crystal sand which is then freed from a red dyestuff by means of ether and finally recrystallised from an alcohol-ether mixture, thus yielding the pure 1- phenyl 2 methyl 3 carbomethoxy amino- 4-isopropyl-5-pyrazolone of melting point 126 C.

Example 10 10 parts of the azide of the 1-phenyl-2-methyl- Example 11 1-phenyl-4-secbutyl-5-pyrazolone 3 carboxylic acid ethyl ester, made from 1-phenyl-5- pyrazolone-3-carboxylic acid ethyl ester by hydrogenation in methyl ethyl ketone at 110 C. and at a pressure of 100 atm., and having a melting point of 96 C., is converted, by heating with dimethyl sulfate, into the oily 1-phenyl-2- methyl-4-sec-.butyl-5-pyrazolone 3 carboxylic acid ethyl ester and the same, by heating with hydrazine, transformed into the l-phenyl-Z- methyl-4-sec.butyl5pyrazolone 3 carboxylic acid hydrazlde crystallising out very slowly. (Crystal powder somewhat soluble in water, M. P. 145 C'.) The azide, prepared therefrom according to Example 1, may be obtained from a chloroform-ether mixture in form of well formed crystals of point of decomposition of C. By heating said compound with 10 parts of methanol there is obtained the 1-pheny1-2-methyl-4- sec.butyl-3-carbomethoxy-amino 5 yrazolone melting at 109 C. By boiling with dilute caustic soda lye there is obtained therefrom the 1- phenyl-2-methyl-3-aminol-secbutyl -5- pyrazolone in form of long prisms (M. P. 204 0., when recrystallised from dilute alcohol).

Example 12 1:4 diphenyl-5-pyrazolone-3-carboxylic acid ethyl ester, prepared from phenyl oxalacetic acid diethyl ester withphenyl hydrazine, M. P. 144 0., is converted by heating with dimethyl sulfate into the 1:e-diphenyl-z-methyl-5-pyraZolone-3- carboxylic acid ethyl ester (M. P. 107 C'.) and the latter by heating with hydrazine. into the hydrazide. This compound is obtained in a well crystallised form by triturating with ether; it can be obtained from an alcohol ether mixture with a melting point of 75 C. (escapement of crystal ether) in vacuo at room temperature it becomes greasy, obviously losing crystal ether.

As described in the above examples, there is obtained therefrom the 1:4-diphenyl-2-methyl-5- pyrazolone-ii-carboxylic acid hydrazide (M. P. 97 C., decomposition) and from this compound the 1:4 diphenyl- 2 methyl-3-carbomethoxyamino-S-pyrazolone (M. P.-174-175 C. when recrystallised from alcohol) by heating it in methanol. By alkaline cleavage there results the 1:4- dipheynl-2-methyl-3-amino-5-pyrazolone which, when crystallised from alcohol, yields broad needles of melting point 241 C. When starting from 1:2-dimethyl-4-phenyl-5-pyrazolone-3-carboxylic acid ethyl ester one obtains in exactly the same manner the 1:2-dimethyl-,-4-phenyl-3- amino-5-pyrazolone.

Example 13 I In the same manner as described in Example 2 one obtains, by using benzyl oxalacetic acid diethyl ester through the l-phenyl-4 benzyl-5- pyra zolone-Il-carboxylic acid ethyl ester (M. P. ,195196 C the l-pheny1-2-methyl-4-benzyl 5-pyrazolone-3carboxylic acid ethyl ester, melt-' Eiramqole 14 p-Tolyl hydrazine is converted by means of oxalacetic acid ester into 1-(e-methylphenyl)- 5-pyrazolone-3ecarboxylic acid ethyl ester (melting point188 C.) and this compound transformed byhydrogenation in acetone at 110- C. and under a pressure of 100 atm. into the -l-(4'-methylphen- -yl-4-isopropyl-5 pyrazolone 3 carboxylic acid ethylester (M. P. 110 C.). Byusualmethylation the 1- (4'-methylphenyl) -2-methyl-4isopropyl- .5-pyrazolone-3-carboxylic acid. ethyl ester (melting point 101 C.) is obtained therefrom and converted by means of hydrazine into the hydrazide (melting point 96 0.). Through the azide (melting point 92 C., decomposition) one obtains as in Example 1 the 1(4-methylphenyl) -2-methyl- 3 -carbomethoxy-amino-4-isopropyl-5-pyrazolone (M. P. l91.5 C.) and from this latter by alkaline or acid hydrolysis the 1- 4-methylphenyl) -2- methyl-3-amino-4-isopr0pyl-5-pyrazolone (M. P. 205 C.). If, in the aboveeXample, p-methylcyclohexylor cyclohexyl hydrazine is used in- Example 15 1 2 dimethyl-5-pyrazolone-3-carboxylic acid ethyl ester, obtained from l-methyl-S-pyrazolone-3-carboxylic acid ethyl ester by heating with two molecules of dimethyl sulfate in form of a water-soluble oil which solidifies at a temperature below C., is converted by treating with hydrazine into the hydrazide (melting point 204 C.) which is readily soluble in water, but. difiicultly soluble in absolute alcohol and ether. The azide, made according to Example 1, is watersoluble and can be removed from the solution neutralised with sodium carbonate by means of chloroform. On evaporation of the chloroform the azide remains in form of yellow long needles detonating at 110 C. By heating in methanol the 1 :2-dimethyl-3-carb0methoXy-amino- -pyrazolone of melting point 200 C. is obtained.

The l-benzyl-2methyl-5-pyraz0lone-3-carboxylic acid ethyl ester reacts in exactly the same manner.

Example 16 parts of 1-phenyl-2-methyl-4-isopr0pyl-5- pyrazolone-3-carboxylic acid azide are slowly heats-d up to 90-l00 C. wih 0.5 p r of w trr and 100 parts of toluene until the development of nitrogen has completed, then the toluene is distilled off in vacuo and there is obtained a residue which, for the greater part, consists of l-phenyl- 2-methyl-3-em no-4-isoprooyl-5-pyrozolone and, for the minor part, of bis-(l-phenyl-5-oxy-2- methyl-4-isopropyl-pyrazolidene(-3) urea (melting at 165 C. when recrystallised from alcohol). The whole is either heated with Zn-caustie soda lye, until the urea is saponified and l-phenyl-Z- methyl- 3 -am no-: 4 -is 'orop yl- 5 pyr znlone is present in uniform condition, or the alkali-soluble urea is separated off by stirring with caustic soda lye and precipitated out from the filtrate by means of acids (melting point 165 C.)

The azi'de can also be heated with alcohol containing water, whereby-one obtains a mixture (ill The rest can be recovered which consists of iaminopyrazolone, its urethane and its urea, andwhich-is-preferably saponlfied Example 17 11 parts of 1-phenyl-2-methyl 5-pyrazolone- 3-carboxylic acid amide made from the ethyl ester by allowing the same to stand for 12 hours with alcoholic ammonia, melting point ,197" 'C., are combined with 130 parts by volume of an ice-cold hypochlorite solution-(.mad,e by introducing parts of chlorine into an aqueous solution of 100 parts of caustic soda and filling up to 1000 parts). The dissolution takes place rapidly, whereupon 100 'parts by volume of a .n-caustic soda lye are added tothe solution and the whole is allowed to stand for half an hour and heated for a short time on the water-bath. l-phenyl- 2-methyl-3-amino- 5-pyrazolone precipitates out. by evaporation of the neutralised filtrate.

Example "1 s very diflioultly soluble in alcohol), made from the ester by heating up to 130 C. with alcoholic ammonia in a closed vessel, are suspended with 40 parts by volume of alcohol and mixed with parts by volume of hypochlorite solution (made as indicated in Example 17).. Under self-heating all is dissolved. Then, one filters off from a little quantity of non-converted substance, adds 50 parts by volume of n-caustic soda lye thereto and heats up to about C. 1:4-phenyl-2- methyl-3-amino-5-pyrazolone is thus precipitated out.

Instead of the amides or azides there may also be used in the above examples the reaction prod.- uctsfrom the carboxylic acids, esters, halides etc. with hydrazoic acid, as it is described in the British Patent No. 307,798.

What we claim is:

1. The 2-alkyl-3-amino-5-pyrazolones in which the B-amino substituent is selected from the group consisting of --NH2, -NH.C0.0.alky1 and 3. The 3-carbalkoxyamino-2-alkyl-5-pyrazolones.

4. The 1-phenyl-2-methyl-3-amino-4-isopropyl-5-pyrazolone.

5. The 1-phenyl-2-methyl-B-carbomethoxyamino-4-isopropyl-5-pyrazolone.

HANS STENZL. ALFRED STAUB. 

